ArticleGenetics in medicine : official journal of the American College of Medical Genetics2024
Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 5 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
5 citing papers in PubMed, 9 citations in OpenAlex.
- Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.NPJ genomic medicine · 2026Article
- A bioinformatic survey of RNA isoform diversity and expression across 9 GTEx tissues using long-read sequencing data.BMC genomics · 2025Article
- Article
- BiallelicBrain communications · 2025Article
- Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations.Nature genetics · 2024Article
Corrections and comments
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Authors and funding
52 authors at 20 institutions in 3 countries.
Funding
Abstract
purposeWe sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.
methodsThe impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.
resultsBiallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors.
conclusionThis patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
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